Atherosclerosis is the pathological basis for ischemic cardiovascular disease (CVD), the leading cause of death in the industrialized nations. Two lines of evidence indicate that high levels of plasma high-density lipoprotein cholesterol (HDL-C) protect against CVD. First, epidemiological studies have shown an inverse relationship between HDL-C levels and the incidence of CVD. Second, raising plasma HDL-C levels is associated with reduced atherosclerosis in mice, rabbits and humans. Because plasma HDL-C levels are largely genetically determined, quantitative trait locus (QTL) mapping has been used to localize HDL-regulating chromosomal (Chr) loci. Comparison of mouse and human HDL QTLs revealed that they are concordant, therefore finding genes underlying HDL-C QTLs in mice may reveal HDL-regulating genes in humans, which may provide therapeutic targets. Our long-term objective is to find new genes regulating plasma HDL-C levels to provide new therapeutic targets for CVD. In this proposal, we have chosen to identify the genes for one HDL-C QTL on Chr 1 (Hdlq33) and one on Chr 6 (Hdlq12) based on the following criteria: 1) at least one human homologous HDL-C QTL has been found;2) the QTL has been found in multiple crosses, and/or they coincide with in silico HDL-C QTLs;3) the QTL can be separated from closely linked QTL(s) so we know which crosses have detected the QTL we want to study;4) the crosses involve sequenced strains (B6, A, DBA/2 and 129) because sequence differences will then be easier to find;and 5) other genetic resources are available: congenic strains, consomic strains, recombinant inbred strains. We propose to identify the genes of these two QTLs through the following specific aims. First, we will narrow the QTLs using genomic, statistical and bioinformatic tools. Second, we will narrow the QTLs genetically. Third, we will test candidate genes in mice according to their sequence, expression and functions, and test their relevance to human CVD in association studies. Through this grant, we will find genes that regulate blood HDL cholesterol (the so-called "good cholesterol") levels. Drugs acting on these genes may increase HDL cholesterol, and decrease the incidence of cardiovascular disease.